ABSTRACT Chronic Kidney Disease (CKD) is increasingly recognized as a major comorbid condition in older adults. The burden of CKD is predominantly due to its adverse physiological effects that promote cardiovascular disease, heart failure, physical and cognitive functional declines, bone disease, and death. Extensive observational research has shown that physical inactivity is a consistent risk factor for progressive kidney disease in older adults. However, no large, randomized controlled trial (RCT) has ever been attempted with the objective of preventing or treating age-related kidney disease. The Lifestyle Interventions and Independence for Elders (LIFE) trial demonstrated that a structured physical activity intervention can reduce the incidence of disability compared with a health education control intervention. Now that it has been completed, the LIFE trial offers an ideal and efficient opportunity to test whether a physical activity intervention can improve kidney health in elders in an RCT setting. Our study proposes to transform LIFE into the first large trial among elders to evaluate the impact of exercise on kidney health, utilizing stored blood and urine specimens that have been serially collected from baseline to 24 months. This proposal will add a comprehensive set of serum and urine biomarkers that comprise measures of both glomerular and tubular function and injury; these will be repeated at baseline, year 1 and year 2 in 1,264 participants equally balanced between the two arms of the RCT. Aim 1 will determine the efficacy of randomization to the prescribed physical activity intervention on measures of kidney health compared with the control arm of the LIFE trial. Aim 2 will evaluate the effectiveness of achieved exercise frequency and intensity during the trial on measures of kidney health, and we will also investigate effect modification by key demographic and clinical subgroups. In Aim 3, we will explore whether heterogeneity of mitochondrial DNA across individuals impacts the kidney?s response to exercise, using existing mitochondrial DNA sequence data in LIFE participants. In summary, this proposal will transform the LIFE study to allow determination of whether age-related kidney disease can be prevented in sedentary elders by a structured exercise intervention, and to evaluate the optimal exercise intensity and target population.